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Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer.

ABSTRACT: In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite initial responses and long-lasting remissions, resistance to tyrosine kinase inhibitors invariably develops, most commonly due to the emergence of secondary T790M mutations or to the amplification of mesenchymal-epithelial transition factor (c-Met), which inevitably leads to treatment failure. Several clinical studies are ongoing (http://www.clinicaltrials.gov), aimed to evaluate the efficacy and toxicity of combined approaches and to develop novel irreversible or multitargeted tyrosine kinase inhibitors and mutant-selective inhibitors to overcome such resistance. This review is an overview of ongoing Phase I, II, and III trials of novel small molecule epidermal growth factor receptor inhibitors and combinations in non-small cell lung cancer patients.

SUBMITTER: Berardi R

PROVIDER: S-EPMC3665567 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer.

Berardi Rossana R Santoni Matteo M Morgese Francesca F Ballatore Zelmira Z Savini Agnese A Onofri Azzurra A Mazzanti Paola P Pistelli Mirco M Pierantoni Chiara C De Lisa Mariagrazia M Caramanti Miriam M Pagliaretta Silvia S Pellei Chiara C Cascinu Stefano S

OncoTargets and therapy 20130521

In the last decade, better understanding of the role of epidermal growth factor receptor in the pathogenesis and progression of non-small cell lung cancer has led to a revolution in the work-up of these neoplasms. Tyrosine kinase inhibitors, such as erlotinib and gefitinib, have been approved for the treatment of non-small cell lung cancer, demonstrating an improvement in progression-free and overall survival, particularly in patients harboring activating EGFR mutations. Nevertheless, despite in ...[more]

PMID: 23723712

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Project description:Background: Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer morbidity and mortality worldwide. In the present study, we identified novel biomarkers associated with the pathogenesis of NSCLC aiming to provide new diagnostic and therapeutic approaches for NSCLC. Methods: The microarray datasets of GSE18842, GSE30219, GSE31210, GSE32863 and GSE40791 from Gene Expression Omnibus database were downloaded. The differential expressed genes (DEGs) between NSCLC and normal samples were identified by limma package. The construction of protein-protein interaction (PPI) network, module analysis and enrichment analysis were performed using bioinformatics tools. The expression and prognostic values of hub genes were validated by GEPIA database and real-time quantitative PCR. Based on these DEGs, the candidate small molecules for NSCLC were identified by the CMap database. Results: A total of 408 overlapping DEGs including 109 up-regulated and 296 down-regulated genes were identified; 300 nodes and 1283 interactions were obtained from the PPI network. The most significant biological process and pathway enrichment of DEGs were response to wounding and cell adhesion molecules, respectively. Six DEGs (PTTG1, TYMS, ECT2, COL1A1, SPP1 and CDCA5) which significantly up-regulated in NSCLC tissues, were selected as hub genes according to the results of module analysis. The GEPIA database further confirmed that patients with higher expression levels of these hub genes experienced a shorter overall survival. Additionally, CMap predicted the 20 most significant small molecules as potential therapeutic drugs for NSCLC. DL-thiorphan was the most promising small molecule to reverse the NSCLC gene expression. Conclusions: Based on the gene expression profiles of 696 NSCLC samples and 237 normal samples, we first revealed that PTTG1, TYMS, ECT2, COL1A1, SPP1 and CDCA5 could act as the promising novel diagnostic and therapeutic targets for NSCLC. Our work will contribute to clarifying the molecular mechanisms of NSCLC initiation and progression.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) have become a standard care in non-small-cell lung cancer (NSCLC). However, its application to epidermal growth factor receptor (EGFR)-mutant NSCLC patients is confronted with drug resistance. This study aimed to clarify the potential role of Yes1-associated transcriptional regulator (YAP1) in ICIs treatment for EGFR-mutant NSCLC population.MethodsAll the clinical data of NSCLC were downloaded from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) for GSE11969 and GSE72094. Based on YAP1 expression, all the NSCLC patients including the EGFR-mutant and EGFR-wildtype (WT) patients were divided into two groups, YAP1_High and YAP1_Low. Using cBioPortal, genetic alterations were analyzed for identification of immunogenicity in EGFR-mutant NSCLC. MR analysis was used to analyze the hub gene of EGFR. The infiltration of immune cells and the expression of the identified tumor-associated antigens were identified with TIMER. By graph learning-based dimensionality reduction analysis, the immune landscape was visualized. Moreover, survival analysis was performed to verify the predictive value of YAP1 in ICIs treatment for EGFR-mutant NSCLC population using Ren's research data (NCT03513666).ResultsYAP1 was a poor prognostic factor of EGFR-mutant NSCLC population rather than lung adenocarcinoma (LUAD) patients. MR analysis revealed that the EGFR gene regulated YAP1 expression. YAP1 was identified as a hub gene closely associated with immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population in TCGA LUAD. Tumors with YAP1_High showed an immune-"cold" and immunosuppressive phenotype, whereas those with YAP1_Low demonstrated an immune-"hot" and immunoactive phenotype. More importantly, it was verified that YAP1_High subpopulation had a significantly shorter progression-free survival (PFS) and overall survival (OS) after ICIs treatment in EGFR-mutant NSCLC patients in the clinical trial.ConclusionsYAP1 mediates immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population. YAP1 is a novel negative biomarker of ICIs treatment in EGFR-mutant NSCLC population. Clinical Trials. This trial is registered with NCT03513666.

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Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer.

Publications

Novel small molecule EGFR inhibitors as candidate drugs in non-small cell lung cancer.

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